EP1244671A1 - Triazolo-pyrimidine derivatives as ligands for gaba receptors - Google Patents

Abstract

A class of substituted or 6,7-ring fused [1, 2, 3]triazolo[1,5- alpha ]-pyrimidine derivatives, possessing an optionally substituted cycloalkyl, phenyl or heteroaryl substituent at the 3-position and an amino moiety at the 5-position, are selective ligands for GABAA receptors, in particular having high affinity for the alpha 2 and/or alpha 3 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of disorders of the central nervous system, including anxiety and convulsions.

Description

TRIAZOLO-PYRIMIDINE DERIVATIVES AS LIGANDS FOR GABA

RECEPTORS

The present invention relates to a class of substituted triazolo- pyrimidine derivatives and to their use in therapy. More particularly, this invention is concerned with substituted [l,2,3]triazolo[l,5-α]pyrimidine derivatives which are ligands for GABAA receptors and are therefore useful in the therapy of deleterious mental states.

Receptors for the major inhibitory neurotransmitter, gamma- aminobutyric acid (GABA), are divided into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to include at least six α subunits, four β subunits, three γ subunits, one δ subunit, one ε subunit and two p subunits.

Although knowledge of the diversity of the GABAA receptor gene family represents a huge step forward in our understanding of this ligand- gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an α subunit, a β subunit and a γ subunit constitute the minimum requirement for forming a fully functional GABAA receptor expressed by transiently transfecting cDNAs into cells. As indicated above, δ, ε and p subunits also exist, but are present only to a minor extent in GABAA receptor populations.

Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABAA receptor exists in pentameric form. The selection of at least one α, one β and one γ subunit from a repertoire of seventeen allows for the possible existence of more than 10,000 pentameric subunit combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits).

Receptor subtype assemblies which do exist include, amongst many others, αlβ2γ2, α2β2/3γ2, α3βγ2/3, α2βγl, α5β3γ2/3, α6βγ2, α6βδ and α4βδ. Subtype assemblies containing an αl subunit are present in most areas of the brain and are thought to account for over 40% of GABAA receptors in the rat. Subtype assemblies containing α2 and α3 subunits respectively are thought to account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an α5 subunit are expressed predominantly in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat.

A characteristic property of all known GABAA receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine (BZ) binding site. The BZ binding site is the most explored of the GABAA receptor modulatory sites, and is the site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABAA receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the αl subunit in combination with a β subunit and γ2. This is the most abundant GABAA receptor subtype, and is believed to represent almost half of all GABAA receptors in the brain. Two other major populations are the α2βγ2 and α3βγ2/3 subtypes.

Together these constitute approximately a further 35% of the total GABAA receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain α5-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonists or antagonists were known.

It is now believed that agents acting as BZ agonists at αlβγ2, α2βγ2 or α3βγ2 subtypes will possess desirable anxiolytic properties. Compounds which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as BZ agonists are referred to hereinafter as "GABA_A receptor agonists". The αl-selective GABAA receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZ1 binding site is mediated through GABAA receptors containing the αl subunit. Accordingly, it is considered that GABAA receptor agonists which interact more favourably with the α2 and/or α3 subunit than with αl will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Also, agents which are antagonists or inverse agonists at αl might be employed to reverse sedation or hypnosis caused by αl agonists.

The compounds of the present invention, being selective ligands for GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder; psychotic disorders including schizophrenia; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivity disorder; and disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work. Further disorders for which selective ligands for GABAA receptors may be of benefit include pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; and hearing loss. Selective ligands for GABAA receptors may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy. WO 99/37645 describes a class of substituted and 7,8-ring fused

[l,2,4]triazolo[4,3-b]pyridazine derivatives which are stated to be selective ligands for GABAA receptors beneficial in the treatment and/or prevention of neurological disorders including anxiety and convulsions. There is in that publication, however, no disclosure nor any suggestion that the central triazolo-pyridazine ring system can be replaced by any other ring system. In particular, there is no disclosure nor any suggestion in that publication that the specified triazolo-pyridazine ring system can be replaced by a [l,2,3]triazolo[l,5-α]pyrimidine ring system.

Co-pending International Patent Application No. PCT/GB99/01827, published on 23 December 1999 as WO 99/65907, describes a class of substituted and 6,7-ring fused [l,2,3]triazolo[l,5- ]pyrimidine derivatives which are stated to be selective ligands for GABAA receptors beneficial in the treatment and/or prevention of neurological disorders including anxiety and convulsions. However, the compounds described therein all possess a substituted alkoxy moiety at the 5-position, none of the compounds described therein being substituted at the 5-position by a substituted amino moiety.

The present invention provides a class of triazolo-pyrimidine derivatives which possess desirable binding properties at various GABAA receptor subtypes. The compounds in accordance with the present invention have good affinity as ligands for the α2 and/or α3 subunit of the human GABAA receptor. The compounds of this invention may interact more favourably with the α2 and/or α3 subunit than with the αl subunit. Desirably, the compounds of the invention will exhibit functional selectivity in terms of a selective efficacy for the α2 and/or α3 subunit relative to the αl subunit.

The compounds of the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the α2 and/or α3 subunit, as measured in the assay described hereinbelow, of 100 nM or less, typically of 50 nM or less, and ideally of 10 nM or less. The compounds in accordance with this invention may possess at least a 2-fold, suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the α2 and/or α3 subunit relative to the αl subunit. However, compounds which are not selective in terms of their binding affinity for the α2 and/or α3 subunit relative to the αl subunit are also encompassed within the scope of the present invention; such compounds will desirably exhibit functional selectivity in terms of a selective efficacy for the α2 and/or α3 subunit relative to the αl subunit.

The present invention provides a compound of formula I, or a salt or prodrug thereof:

,. N _

2^/ ' \ _ 3

R

(I)

wherein

Y represents hydrogen or C_I-G alkyl; and Z represents Ci-β alkyl, C3-7 cycloalkyl, C .₇ cycloalkenyl, CG-₈ bicycloalkyl, aryl, C3-7 heterocycloalkyl, heteroaryl, C2-7 alkoxycarbonyl or di(C_1-6)alkylamino, any of which groups may be optionally substituted; or

Y and Z are taken together with the two intervening carbon atoms to form a ring selected from C5-9 cycloalkenyl, CG-IO bicycloalkenyl, tetrahydropyridinyl, pyridinyl and phenyl, any of which rings may be optionally benzo-fused and/or substituted;

R¹ represents C3-7 cycloalkyl, phenyl, furyl, thienyl or pyridinyl, any of which groups may be optionally substituted;

R² represents hydrogen, Ci-G alkyl, hydroxy(C₁-e) alkyl or Ci-β alkoxy(C₁-G)alkyl; and

R³ represents Ci-c alkyl, C3-7 cycloalkyl(C]-G)alkyl, aryl(C₁-G)alkyl, C3-7 heterocycloalkyl or any of which groups may be optionally substituted; or

R² and R³ are taken together with the intervening nitrogen atom to form a ring of formula (a), (b), (c), (d), (e), (f), (g), (h), (j) or (k):

(a) (b) (c) (d)

(e) ( ) (g) (h)

Q⁾ 00

wherein

X represents oxygen, sulphur, N-R⁵ or CR⁶R⁷; R⁴ represents hydrogen, Ci-β alkyl, aryl, C2-7 alkoxycarbonyl or aryl(C₁-6)alkoxy(C₁-6)alkyl;

R⁵ represents hydrogen, Ci-G alkyl, di(C₁-G)alkylamino(C₁-G)alkyl, C₂-_G alkenyl, C3-7 cycloalkyl(C₁-6)alkyl, aryl, C3-7 heterocycloalkyl(Cι-6)alkyl, heteroaryl, C2-7 alkylcarbonyl or C2-7 alkoxycarbonyl; R⁶ represents hydrogen, halogen, hydroxy, CI-G alkoxy, di(C₁-G)alkylamino, C2-7 alkoxycarbonyl, or an optionally substituted or phenyl ring-fused C3-7 heterocycloalkyl group; and

R⁷ represents hydrogen, Ci-c alkyl, or an optionally substituted aryl or aryl(C₁-G)alkyl group. The present invention also provides a compound of formula I as depicted above, or a salt or prodrug thereof, wherein Y, Z and R¹ are as defined above;

R² represents hydrogen, Ci-6 alkyl, hydroxy(C -6) alkyl or Ci-c alkoxy(C₁-6)alkyl; and R³ represents Ci-β alkyl, C3-7 cycloalkyl(Cι-G)alkyl, aryl(C₁-6)alkyl or heteroaryl(C₁-6)alkyl, any of which groups may be optionally substituted; or

R² and R³ are taken together with the intervening nitrogen atom to form a ring of formula (a), (b), (c), (d), (e), (f), (g) or (h) as depicted above, wherein

X, R⁴ and R⁷ are as defined above; R⁵ represents hydrogen, Ci-G alkyl, C2-6 alkenyl, aryl, heteroaryl, C₂-₇ alkylcarbonyl or C2-7 alkoxycarbonyl; and

R^G represents hydrogen, halogen, hydroxy, di(C₁-G)alkylamino, C₃-₇ heterocycloalkyl or C2-7 alkoxycarbonyl. Where Y and Z are taken together with the two intervening carbon atoms to form a ring, the resulting compounds of formula I above incorporate the relevant cycloalkenyl, bicycloalkenyl, tetrahydropyridinyl, pyridinyl or phenyl ring fused to the central triazolo-pyrimidine ring system as depicted in formula I. Where Y and Z are taken together with the two intervening carbon atoms to form a C5-9 cycloalkenyl ring, this ring may be a cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl or cyclononenyl ring, suitably cyclohexenyl or cycloheptenyl.

Where Y and Z are taken together with the two intervening carbon atoms to form a CG-IO bicycloalkenyl ring, this ring may be a bicyclo[2.1.1]hex-2-enyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]oct-2-enyl, bicyclo[3.2.2]non-6-enyl or bicyclo[3.3.2]dec-9-enyl ring, suitably bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]oct-2-enyl or bicyclo[3.2.2]non-6- enyl, and especially bicyclo[2.2.2]oct-2-enyl. Where Y and Z are taken together with the two intervening carbon atoms to form a ring, this ring may be optionally benzo-fused. By way of illustration, Y and Z taken together with the two intervening carbon atoms may represent a benzo-fused cyclohexenyl ring, whereby the resulting ring is dihydronaphthyl. The groups Y, Z, R¹, R³, R^G and R⁷ may be unsubstituted, or substituted by one or more, suitably by one or two, substituents. In general, the groups Y, Z, R¹, R³, R⁶ and R⁷ will be unsubstituted or monosubstituted. Examples of optional substituents on the groups Y, Z, R¹, R³, R⁶ and R⁷ include Ci-G alkyl, aryl(C₁-₆)alkyl, pyridyl(Cι-₆)alkyl, halogen, halo(Cι-G)alkyl, cyano, cyano(Cι-G)alkyl, hydroxy, hydroxymethyl, Ci-6 alkoxy, C3-7 cycloalkyl(C₁-G)alkoxy, C3-7 cycloalkoxy, amino(C__-6)alkyl, di(C₁-_G)alkylamino(C₁-6)alkyl, di(Ci-6)alkylaminocarbonyl(Ci-G)alkyl, N-(C₁-_G)alkylpiperidinyl, pyrrolidinyl(Cι-G)alkyl, piperazinyl(C₁-G)alkyl, morpholinyl(Ci-G)alkyl, di(Ci-6)alkylmorpholinyl(C]-G)alkyl and imidazolyl(C₁-G)alkyl. Representative substituents include CI-_G alkyl, aryl(C₁-6)alkyl, halogen, cyano, hydroxy, hydroxymethyl, Ci-G alkoxy and C3-7 cycloalkyl(C₁-6)alkoxy. Particular substituents include methyl, ethyl, fluoro, chloro, hydroxy and methoxy. Additional substituents include oxo; and C2-7 alkoxycarbonyl, e.g. methoxycarbonyl or ethoxycarbonyl. Specific substituents include methyl, fluoro, hydroxy, methoxy, oxo and ethoxycarbonyl.

As used herein, the expression "Ci-G alkyl" includes methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, 71-propyl, isopropyl, teri-butyl and 1,1-dimethylpropyl. Derived expressions such as "CI-_G alkoxy" are to be construed accordingly.

Typical C2-G alkenyl groups include vinyl and allyl.

Typical C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The expression "C3-7 cycloalkyl(Ci-6)alkyl" as used herein includes cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

Typical C -7 cycloalkenyl groups include cyclobutenyl, cyclopentenyl and cyclohexenyl.

Typical aryl groups include phenyl and naphthyl, preferably phenyl. The expression "aryl(Ci-G)alkyl" as used herein includes benzyl, phenylethyl, phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and diazepanyl groups. A typical phenyl ring-fused C3-7 heterocycloalkyl group is 1,2,3,4- tetrahydroisoquinolinyl. A typical C3-7 heterocycloalkyl(Ci-G)alkyl group is pyrrolidinylethyl. Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.

The expression "heteroaryl(Ci-6)alkyl" as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine or chlorine.

For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.

The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.

Suitably, Y represents hydrogen or methyl, especially hydrogen.

Examples of suitable values for the substituent Z include methyl, ethyl, isopropyl, terf-butyl, 1,1-dimethylpropyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, cyclobutenyl, bicyclo[2.1.1]hex-l-yl, bicyclo[2.2.1]heptan-l-yl, phenyl, pyrrolidinyl, methyl-pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyridinyl, furyl, thienyl, chloro-thienyl, methoxycarbonyl and diethylamino, especially tert-bntyl, cyclobutyl or phenyl.

In a particular embodiment, the substituent Z represents C3-7 cycloalkyl, either unsubstituted or substituted by Ci-G alkyl, especially methyl. Favourably, Z represents cyclobutyl.

When Y and Z are taken together with the two intervening carbon atoms to form a ring, representative compounds according to the invention include those of structure IA to IL:

(IA) (IB) (IC)

(ID) (IE) (IF)

(IG) (IH)

wherein R¹, R² and R³ are as defined above;

R⁸ represents hydrogen, CI-G alkyl, aryl(Cι-6)alkyl, halogen, cyano, hydroxy, hydroxymethyl or d-G alkoxy; and

R⁹ represents hydrogen or d-6 alkyl.

Suitably, R⁸ represents hydrogen, d-6 alkyl or halogen, especially hydrogen, methyl, fluoro or chloro. Particular values of R⁸ include hydrogen and fluoro, especially hydrogen.

Suitably, R⁹ represents hydrogen or methyl. Favoured ring-fused triazolo-pyrimidine derivatives according to the present invention include the compounds represented by formula IL as depicted above.

Examples of typical optional substituents on the group R¹ include methyl, fluoro and methoxy, especially fluoro.

Representative values of R¹ include cyclopropyl, phenyl, methylphenyl, fluorophenyl, difluorophenyl, trifluorophenyl, methoxyphenyl, furyl, thienyl, methyl-thienyl and pyridinyl. More particularly, R¹ may represent unsubstituted or monosubstituted phenyl. Most particularly, R¹ represents phenyl or fluorophenyl, especially fluorophenyl. A specific value of R¹ is 2-fluorophenyl.

Suitably, R² represents hydrogen, methyl, hydroxyethyl or methoxyethyl. Specific values of R² include 2-hydroxyethyl and 2- methoxyethyl. Suitably, R³ represents aryl(d-G) alkyl or heteroaryl(Cι-G) alkyl, either of which groups may be optionally substituted.

Suitable values for the substituent R³ in the compounds according to the invention include cyclohexylmethyl, benzyl, pyrazolylmethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, benzimidazolylmethyl, oxadiazolylmethyl, triazofylmethyl, tetrazolylmethyl, pyridinylmethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl, any of which groups may be optionally substituted by one or more substituents. Suitably, R³ represents an optionally substituted triazolylmethyl group.

Examples of suitable optional substituents on the group R³ include d-G alkyl, aryl(Cι-6) alkyl, pyridyl(d-6) alkyl, halogen, halo(Cι-6)alkyl, cyano, cyano(d-G)alkyl, hydroxymethyl, d-o alkoxy, C3-7 cycloalkyl(Cι-G)alkoxy, amino(d-G)alkyl, di(C₁-G)alkylamino(Cι-G)alkyl, di(Ci-6)alkylaminocarbonyl(Ci-6)alkyl, N-(Cι-6)alkylpiperidinyl, pyrrolidinyl(Ci-6)alkyl, piperazinyl(Ci-6)alkyl, morpholinyl(Ci-G)alkyl and di(Cι-_G)alkylmorpholinyl(Ci-6)alkyl, especially C_I-_G alkyl.

Specific illustrations of particular substituents on the group R³ include methyl, ethyl, 7t-propyl, benzyl, pyridinylmethyl, chloro, chloromethyl, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl, morpholinylmethyl and dimethylmorpholinylmethyl, especially methyl or ethyl, and more especially methyl.

Representative values of R³ include hydroxymethyl - cyclohexylmethyl, cyanobenzyl, hydroxymethyl-benzyl, pyrazolylmethyl, dimethyl-pyrazolylmethyl, methyl-isoxazolylmethyl, thiazolylmethyl, methyl-thiazolylmethyl, ethyl-thiazolylmethyl, methyl-thiazolylethyl, imidazolylmethyl, methyl-imidazolylmethyl, ethyl-imidazolylmethyl, benzyl-imidazolylmethyl, benzimidazolylmethyl, methyl- oxadiazolylmethyl, triazolylmethyl, methyl-triazolylmethyl, ethyl- triazolylmethyl, propyl-triazolylmethyl, benzyl-triazolylmethyl, pyridinylmethyl-triazolylmethyl, cyanomethyl-triazolylmethyl, dimethylaminomethyl-triazolylmethyl, aminoethyl-triazolylmethyl, dimethylaminoethyl-triazolylmethyl, dimethylaminocarbonylmethyl- triazolylmethyl, N-methylpiperidinyl-triazolylmethyl, pyrrolidinylethyl- triazolylmethyl, piperazinylethyl-triazolylmethyl, morpholinylethyl- triazolylmethyl, methyl-tetrazolylmethyl, pyridinylmethyl, methyl- pyridinylmethyl, dimethyl-pyridinylmethyl, ethoxy-pyridinylmethyl, cyclopropylmethoxy-pyridinylmethyl, pyridazinylmethyl, chloro- pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.

Particular values of R³ include methyl-triazolylmethyl and ethyl- triazolylmethyl.

A favoured value of R³ is methyl-triazolylmethyl. In an alternative embodiment, R³ suitably represents a substituted d-6 alkyl group. In a particular aspect of this embodiment, R³ represents ethyl substituted by hydroxy or methoxy. Specific values of R³ in this context include 2-hydroxyethyl and 2-methoxyethyl. In a further embodiment, R³ suitably represents an optionally substituted C3-7 heterocycloalkyl group. In a particular aspect of this embodiment, R³ represents piperidinyl, either unsubstituted or substituted by d-G alkyl, e.g. methyl. A specific value of R³ in this context is l-methylpiperidin-4-yl. Where R² and R³ are taken together with the intervening nitrogen atom to form a ring, this is suitably a ring of formula (a), (b), (d), (f), (g) or (h) as depicted above.

Suitably, R⁴ may represent hydrogen or C2-7 alkoxycarbonyl. Particular values of R⁴ include hydrogen and ethoxycarbonyl, especially hydrogen.

Suitably, R⁵ may represent hydrogen, d-c alkyl, aryl or heteroaryl. Typical values of R⁵ include hydrogen, methyl, ethyl, /ι-propyl, dimethylaminoethyl, allyl, cyclopropylmethyl, phenyl, pyrrolidinylethyl, pyridinyl, acetyl, propionyl, trimethylacetyl and ethoxycarbonyl. Specific values of R⁵ include hydrogen, methyl, ethyl, /i-propyl, allyl, phenyl, pyridinyl, acetyl, propionyl, trimethylacetyl and ethoxycarbonyl. Particular values of R⁵ include hydrogen, methyl, phenyl and pyridinyl.

Suitably, R⁶ may represent hydrogen, hydroxy, di(d-G)alkylamino, C3-7 heterocycloalkyl or C2-7 alkoxycarbonyl. Typical values of R^G include hydrogen, hydroxy, methoxy, dimethylamino, pyrrolidinyl, piperidinyl, ethoxycarbonyl-piperidinyl, morpholinyl, diazepanonyl, 1,2,3,4- tetrahydroisoquinolinyl and ethoxycarbonyl. Particular values of R^G include hydrogen, hydroxy, dimethylamino, pyrrolidinyl, piperidinyl and ethoxycarbonyl. An example of a typical optional substituent on the group R⁷ is halogen, suitably chloro. Particular values of R⁷ include hydrogen and d-6 alkyl, especially hydrogen or methyl.

A particular sub-class of compounds according to the invention is represented by the compounds of formula IIA, and salts and prodrugs thereof:

(IIA)

wherein

R¹ is as defined above;

R¹⁸ represents hydrogen or halogen; and

Q represents the residue of a ring of formula (a), (b), (c), (d), (e), (f), (g), (h), (j) or (k) as defined with reference to formula I above.

The present invention also provides a compound of formula IIA as depicted above, or a salt or prodrug thereof, wherein

R¹ and R¹⁸ are as defined above; and

Q represents the residue of a ring of formula (a) to (h) as defined with reference to formula I above.

Particular values of R¹⁸ include hydrogen and fluoro, especially hydrogen.

Particular rings of which Q is the residue include the rings of formula (a), (b), (d), (f), (g) and (h) as depicted above.

A further sub-class of compounds according to the invention is represented by the compounds of formula IIB, and salts and prodrugs thereof:

(IIB)

wherein

R¹ and R² are as defined with reference to formula I above; R¹⁸ is as defined with reference to formula IIA above; n is 1 or 2; and

R¹³ represents hydroxy or d-e alkoxy, or an optionally substituted aryl or heteroaryl group.

In one embodiment of the compounds of formula IIB above, n is 2, and R¹³ represents hydroxy or d-e alkoxy. In a particular aspect of this embodiment, n is 2, and R¹³ represents hydroxy or methoxy.

In another embodiment of the compounds of formula IIB, n is 1 or 2, typically 1, and R¹³ represents an optionally substituted aryl or heteroaryl group. Suitably, R¹³ represents phenyl, pyrazolyl, isoxazolyl, thiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl or quinoxalinyl, any of which groups may be optionally substituted.

A particular value of R¹³ is optionally substituted triazolyl. Examples of typical substituents on the group R¹³ include d-e alkyl, aryl(d-G)alkyl, pyridyl(d-G)alkyl, halogen, cyano, cyano(Cι-r,)alkyl, hydroxymethyl, d-6 alkoxy, C3-7 cycloalkyl(Ci-6)alkoxy, di(Cι-6)alkylamino(Cι-6)alkyl, amino(d-6)alkyl, di(Ci-6)alkylaminocarbonyl(Ci-6)alkyl, iV-(d-6)alkylpiperidinyl, pyrrolidinyl(d-6)alkyl, piperazinyl(C₁-G)alkyl and morpholinyl(d-_G)alkyl, especially Ci-G alkyl.

Illustrative values of specific substituents on the group R¹³ include methyl, ethyl, n.-propyl, benzyl, pyridinylmethyl, chloro, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl and morpholinylmethyl, especially methyl or ethyl, and more especially methyl. Representative values of R¹³ include cyanophenyl, hydroxymethyl - phenyl, pyrazolyl, dimethyl-pyrazolyl, methyl-isoxazolyl, thiazolyl, methyl- thiazolyl, ethyl-thiazolyl, imidazolyl, methyl-imidazolyl, ethyl-imidazolyl, benzyl-imidazolyl, benzimidazolyl, methyl-oxadiazolyl, triazolyl, methyl- triazolyl, ethyl-triazolyl, propyl-triazolyl, benzyl-triazolyl, pyridinylmethyl-triazolyl, cyanomethyl-triazolyl, dimethylaminomethyl- triazolyl, aminoethyl-triazolyl, dimethylaminoethyl-triazolyl, dimethylaminocarbonylmethyl-triazolyl, N-methylpiperidinyl-triazolyl, pyrrolidinylethyl-triazolyl, piperazinylethyl-triazolyl, morpholinylethyl- triazolyl, methyl-tetrazolyl, pyridinyl, methyl-pyridinyl, dimethyl- pyridinyl, ethoxy-pyridinyl, cyclopropylmethoxy-pyridinyl, pyridazinyl, chloro-pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl and quinoxalinyl.

Particular values of R¹³ include methyl-triazolyl and ethyl-triazolyl. A favoured value of R¹³ is methyl-triazolyl. A particular subset of the compounds of formula IIB above is represented by the compounds of formula IIC, and pharmaceutically acceptable salts thereof:

wherein

R¹ and R² are as defined with reference to formula I above;

R¹⁸ is as defined with reference to formula IIA above; and

R²³ represents hydrogen, methyl or ethyl.

Suitably, R²³ represents methyl or ethyl, especially methyl.

Another sub-class of compounds according to the invention is represented by the compounds of formula IID, and salts and prodrugs thereof:

wherein R¹ and Q are as defined above; and

Z¹ represents d-e alkyl, C3-7 cycloalkyl or aryl, any of which groups may be optionally substituted. Examples of typical substituents on the group Z¹ include Ci-G alkyl, especially methyl.

Illustrative values for the group Z¹ include methyl, ethyl, isopropyl, tert -butyl, 1,1-dimethylpropyl, cyclopropyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl and phenyl.

Particular values of Z¹ include tert -butyl, cyclobutyl and phenyl.

In a specific embodiment, Z¹ represents cyclobutyl. In another embodiment, Z¹ represents phenyl.

An additional sub-class of compounds according to the invention is represented by the compounds of formula HE, and salts and prodrugs thereof:

2/ ^N ^

R^2/ ^(CH₂)_n - R¹

(HE)

wherein

R¹, R², n, R¹³ and Z¹ are as defined above.

A particular subset of the compounds of formula HE above is represented by the compounds of formula IIF, and salts and prodrugs thereof:

. N

R'

NΛΛN ^ N ^R

(IIF)

wherein

R¹ and R² are as defined with reference to formula I above; R²³ is as defined with reference to formula IIC above; and

Z¹ is as defined with reference to formula IID above. Specific compounds within the scope of the present invention include:

3-(2-fluorophenyl)-5-(morpholin-4-yl)-[l,2,3]triazolo[l,5-α]quinazoline; 5-[5,6-dihydroimidazo[l,2-α]pyrazin-7(8H)-yl]-3-(2-fluorophenyl)-

[l,2,3]triazolo[l,5-α]quinazoline;

5-[5,6-dihydroimidazo[l,5-α]pyrazin-7(8H)-yl]-3-(2-fluorophenyl)-

[l,2,3]triazolo[l,5-α]quinazoline;

5-[5,6-dihydro[l,2,4]triazolo[l,5-α]pyrazin-7(8H)-yl]-3-(2-fluorophenyl)- [l,2,3]triazolo[l,5-α]quinazoline;

3-(2-fluorophenyl)-5-(3-oxo-4-phenylpiperazin-l-yl)-[l,2,3]triazolo[l,5- jquinazoline;

5-(4-ethoxycarbonylpiperazin-l-yl)-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- α]quinazoline; 5-(3-ethoxycarbonylpiperidin-l-yl)-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- ]quinazoline;

5-(4-ethoxycarbonylpiperidin-l-yl)-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- jquinazoline; 3-(2-fluorophenyl)-5-(4-hydroxypiperidin-l-yl)-[l,2,3]triazolo[l,5- α]quinazoline;

3-(2-fluorophenyl)-5-[4-(pyridin-4-yl)piperazin-l-yl]-[l,2,3]triazolo[l,5- α]quinazoline; 3-(2-fluorophenyl)-5-[4-(pyridin-2-yl)piperazin-l-yl]-[l,2,3]triazolo[l,5- αjquinazoline;

5-(4-acetylpiperazin-l-yl)-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- αjquinazoline;

3-(2-fluorophenyl)-5-[2-oxopiperazin-4(lH)-yl]-[l,2,3]triazolo[l,5- α]quinazoline;

3-(2-fluorophenyl)-5-(l-methyl-2-oxopiperazin-4-yl)-[l,2,3]triazolo[l,5- α]quinazoline;

5-[5,6-dihydroimidazo[l,2- ]pyrazin-7(8H)-yl]-7-fluoro-3-(2-fluorophenyl)-

[l,2,3]triazolo[l,5- ]quinazoline; 5-[bis(2-methoxyethyl)amino]-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- αjquinazoline;

3-(2-fluorophenyl)-5-(thiomorpholin-4-yl)-[l,2,3]triazolo[l,5-α]quinazoline;

5-[4-(dimethylamino)piperidin-l-yl]-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- ]quinazoline; 3-(2-fluorophenyl)-5-[4-(pyrrolidin-l-yl)piperidin-l-yl]-[l,2,3]triazolo[l,5- ]quinazoline;

3-(2-fluorophenyl)-5-[4-(piperidin-l-yl)piperidin-l-yl]-[l,2,3]triazolo[l,5- α]quinazoline;

5-[bis(2-hydroxyethyl)amino]-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- α]quinazoline;

3-(2-fluorophenyl)-5-(4-oxopiperidin-l-yl)-[l,2,3]triazolo[l,5-α]quinazoline;

5-(l-ethyl-2-oxopiperazin-4-yl)-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- a]quinazoline;

3-(2-fluorophenyl)-5-(2-oxo-l-propylpiperazin-4-yl)-[l,2,3]triazolo[l,5- α]quinazoline; 3-(2-fluorophenyl)-5-[2-oxo-l-(2-propenyl)piperazin-4-yl]-[l,2,3]triazolo- [l,5-α]quinazoline;

3-(2-fluorophenyl)-5-(4-hydroxy-4-methylpiperidin-l-yl)-[l,2,3]triazolo-[l,5- ]quinazoline; l-{4-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin-5-yl]piperazin-l- yl}propan-l-one;

2,2-dimethyl-l-{4-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- ]quinazolin-5- yl]piperazin-l-yl}propan-l-one;

A^r-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- ]quinazolin-5-yl]-A^-methyl-iV-(l- methylpiperidin-4-yl)amine; l-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin-5-yl]-[l,4]diazepan-5- one;

3-(2-fluorophenyl)-5-(piperidin-l-yl)-[l,2,3]triazolo[l,5-α]quinazoline;

3-(2-fluorophenyl)-5-[4-(morpholin-4-yl)piperidin-l-yl]-[l,2,3]triazolo[l,5- αjquinazoline;

4-(2-dimethylaminoethyl)-l-[3-(2-Fluorophenyl)-[l,2,3]triazolo[l,5- α]quinazolin-5-yl]-[l,4]diazepan-5-one; l'-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- ]quinazolin-5-yl]-

[l,4']bipiperidinyl-4-carboxylic acid ethyl ester; 5-[4-(3,4-dihydro-lH-isoquinolin-2-yl)piperidin-l-yl]-3-(2-fluorophenyl)-

[l,2,3]triazolo[l,5-α]quinazoline; l-{l-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin-5-yl]piperidin-4-yl}-

[l,4]diazepan-5-one;

N,N-dimethyl-N-{l-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-a]quinazolin-5- yl]pyrrolidin-3-yl}amine;

3-(2-fluorophenyl)-5-{4-[2-(pyrrolidin-l-yl)ethyl]piperazin-l-yl}-

[l,2,3]triazolo[l,5-α]quinazoline;

3-(2-fluorophenyl)-5-(4-methoxypiperidin-l-yl)-[l,2,3]triazolo[l,5- α]quinazoline; l-cyclopropylmethyl-4- [3-(2-fluorophenyl)- [1,2,3] triazolo [1, 5-α] quinazolin-

5-yl]piperazin-2-one; and salts and prodrugs thereof.

Also provided by the present invention is a method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof.

Further provided by the present invention is a method for the treatment and/or prevention of convulsions (e.g. in a patient suffering from epilepsy or a related disorder) which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof.

The binding affinity (Ki) of the compounds according to the present invention for the α3 subunit of the human GABAA receptor is conveniently as measured in the assay described hereinbelow. The α3 subunit binding affinity (Ki) of the compounds of the invention is ideally 10 nM or less, preferably 2 nM or less, and more preferably 1 nM or less.

The compounds according to the present invention will ideally elicit at least a 40%, preferably at least a 50%, and more preferably at least a 60%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the α3 subunit of the human GABAA receptor. Moreover, the compounds of the invention will ideally elicit at most a 30%, preferably at most a 20%, and more preferably at most a 10%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the αl subunit of the human GABAA receptor.

The potentiation of the GABA EC20 response in stably transfected cell lines expressing the α3 and αl subunits of the human GABAA receptor can conveniently be measured by procedures analogous to the protocol described in Wafford et al, Mol. Pharmacol, 1996, 50, 670-678. The procedure will suitably be carried out utilising cultures of stably transfected eukaryotic cells, typically of stably transfected mouse Ltk- fibroblast cells.

The compounds according to the present invention exhibit anxiolytic activity, as may be demonstrated by a positive response in the elevated plus maze and conditioned suppression of drinking tests (cf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Moreover, the compounds of the invention are substantially non-sedating, as may be confirmed by an appropriate result obtained from the response sensitivity (chain-pulling) test (cf. Bayley et al, J. PsychopharmacoL, 1996, 10, 206-213). The compounds according to the present invention may also exhibit anticonvulsant activity. This can be demonstrated by the ability to block pentylenetetrazole-induced seizures in rats and mice, following a protocol analogous to that described by Bristow et al. in J. Pharmacol. Exp. Ther., 1996, 279, 492-501. In order to elicit their behavioural effects, the compounds of the invention will ideally be brain-penetrant; in other words, these compounds will be capable of crossing the so-called "blood-brain barrier". Preferably, the compounds of the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route. The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. In the treatment of anxiety, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.

The compounds of formula I as defined above may be prepared by a process which comprises reacting a compound of formula III with a compound of formula IN:

(HI) (IV)

wherein Y, Z, R¹, R² and R³ are as defined above, and L¹ represents a suitable leaving group.

The leaving group L¹ is suitably an arylsulphonyloxy group such as p-toluenesulphonyloxy (tosyloxy).

The reaction between compounds III and IV is conveniently effected by stirring the reactants at an elevated temperature under basic conditions, for example triethylamine in N,N-dimethylformamide at a temperature in the region of 50°C.

The intermediates of formula III above wherein L¹ represents tosyloxy may be prepared by reacting a compound of formula V:

(V)

wherein Y, Z and R¹ are as defined above; with a tosylating agent, e.g. a tosyl halide such as tosyl chloride.

The reaction is conveniently carried out by stirring at ambient temperature in the presence of a base such as triethylamine, typically in a solvent such as N,N-dimethylformamide.

The intermediates of formula V above, in particular those wherein Y and Z are taken together with the two intervening carbon atoms to form a ring (e.g. a phenyl ring), may be prepared by reacting an azide derivative of formula VI with an acetonitrile derivative of formula VII:

(VI) (VII)

wherein Y, Z and R¹ are as defined above.

The reaction between compounds VI and VII is conveniently effected under basic conditions in a suitable solvent, for example sodium ethoxide in ethanol, typically at an elevated temperature.

The intermediates of formula VI may be prepared by diazotisation of a compound of formula VIII:

(VIII)

wherein Y and Z are as defined above; followed by displacement with azide ion.

The diazotisation/displacement procedure is conveniently effected by treating compound VIII with sodium nitrite at 0°C in the presence of a mineral acid, e.g. hydrochloric acid, then with sodium azide, typically in the presence of sodium acetate.

In an alternative approach, the intermediates of formula V above, in particular those wherein Y and Z represent pendant groups (i.e. are not taken together with the intervening carbon atoms to form a ring), may be prepared by cyclising a compound of formula IX:

(IX)

wherein Y, Z and R¹ are as defined above, L² represents a suitable leaving group, and Ph is an abbreviation for phenyl.

The leaving group L² is typically a halogen atom, especially chloro.

The cyclisation of compound IX is conveniently effected by treatment with a strong base, e.g. potassium bis(trimethylsilyl)amide, in the presence of a suitable solvent, e.g. tetrahydrofuran, typically at a temperature in the region of -78°C. The intermediates of formula IX may be prepared by reacting a compound of formula X with a compound of formula XI:

wherein Y, Z, R¹ and L² are as defined above, and Hal represents a halogen atom; followed by oxidation of the phenylthio group.

The halogen atom Hal in the compounds of formula XI is typically chloro. The reaction between compounds X and XI is conveniently carried out in a solvent such as N,N-dimethylformamide, typically in the presence of pyridine, and suitably at a temperature in the region of 0°C. Subsequent oxidation of the phenylthio group is conveniently accomplished by treatment with ozone, typically in dichloromethane at a temperature in the region of -78°C.

The intermediates of formula X above may be prepared by reacting a compound of formula VII as defined above with a compound of formula XII:

(XII)

wherein Y is as defined above.

The reaction between compounds VII and XII is conveniently carried out by stirring the reactions in a suitable solvent, e.g. dimethylsulphoxide, typically in the presence of a base such as potassium carbonate.

Where they are not commercially available, the starting materials of formula IV, VII, VIII, XI and XII may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.

It will be understood that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art. For example, a compound of formula I initially obtained wherein R³ is unsubstituted may be converted into a corresponding compound wherein R³ is substituted, typically by standard alkylation procedures, for example by treatment with a haloalkyl derivative in the presence of sodium hydride and NN-dimethylformamide, or with a hydroxyalkyl derivative in the presence of triphenylphosphine and diethyl azodicarboxylate. Furthermore, a compound of formula I initially obtained wherein the R³ substituent is substituted by a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein the R³ substituent is substituted by a di(C.-6)alkylamino moiety by treatment with the appropriate di(d-6)alkylamine, typically with heating in a solvent such as 1,4-dioxane in a sealed tube. A compound of formula I wherein R⁵ is hydrogen initially obtained may be converted into the corresponding compound of formula I wherein R⁵ represents d-6 alkyl, C3-G alkenyl or C3-7 heterocycloalkyl(Cι-6)alkyl, typically by standard alkylation procedures, e.g. by treatment with the appropriate alkyl or alkenyl halide in the presence of a base such as sodium hydride or triethylamine and a solvent such as N,iV-dimethylformamide. Moreover, a compound of formula I wherein R⁵ is hydrogen initially obtained may be converted into the corresponding compound of formula I wherein R^δ represents C2-7 alkoxycarbonyl by conventional acylation procedures, e.g. by treatment with the appropriate acyl halide. A compound of formula I wherein R^G is hydroxy initially obtained may be converted into the corresponding compound of formula I wherein R⁶ represents d-G alkoxy by standard alkylation methods, e.g. by treatment with the appropriate alkyl halide, e.g. methyl iodide, in the presence of sodium hydride and N,N- dimethylacetamide. A compound of formula I initially obtained wherein -NR²R³ represents a ring of formula (d) may be converted by reductive amination into a compound of formula I wherein -NR²R³ represents a ring of formula (a) in which X is CR⁶R⁷, wherein R⁷ is hydrogen and R⁶ represents an N-linked heterocycloalkyl moiety, by treatment with the appropriate heterocycloalkane reagent, e.g. morpholine, in the presence of a reducing agent such as sodium triacetoxyborohydride.

Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds according to the invention. The compounds in accordance with this invention potently inhibit the binding of [³H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the α2 or α3 subunit stably expressed in Ltk- cells.

Reagents

• Phosphate buffered saline (PBS).

• Assay buffer: 10 mM KH₂P0 , 100 mM KCl, pH 7.4 at room temperature.

• [³H]-Flumazenil (18 nM for αlβ3γ2 cells; 18 nM for α2β3γ2 cells; 10 nM for α3β3γ2 cells) in assay buffer. • Flunitrazepam 100 μM in assay buffer.

• Cells resuspended in assay buffer (1 tray to 10 ml).

Harvesting Cells

Supernatant is removed from cells. PBS (approximately 20 ml) is added. The cells are scraped and placed in a 50 ml centrifuge tube. The procedure is repeated with a further 10 ml of PBS to ensure that most of the cells are removed. The cells are pelleted by centrifuging for 20 min at 3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets are resuspended in 10 ml of buffer per tray (25 cm x 25 cm) of cells.

Assay

Can be carried out in deep 96-well plates or in tubes. Each tube contains:

• 300 μl of assay buffer. • 50 μl of [³H]-flumazenil (final concentration for αlβ3γ2: 1.8 nM; for α2β3γ2: 1.8 nM; for α3β3γ2: 1.0 nM). • 50 μl of buffer or solvent carrier (e.g. 10% DMSO) if compounds are dissolved in 10% DMSO (total); test compound or flunitrazepam (to determine non-specific binding), 10 μM final concentration.

• 100 μl of cells. Assays are incubated for 1 hour at 40°C, then filtered using either a

Tomtec or Brandel cell harvester onto GF/B filters followed by 3 x 3 ml washes with ice cold assay buffer. Filters are dried and counted by liquid scintillation counting. Expected values for total binding are 3000-4000 dpm for total counts and less than 200 dpm for non-specific binding if using liquid scintillation counting, or 1500-2000 dpm for total counts and less than 200 dpm for non-specific binding if counting with meltilex solid scintillant. Binding parameters are determined by non-linear least squares regression analysis, from which the inhibition constant Ki can be calculated for each test compound. The compounds of the accompanying Examples were tested in the above assay, and all were found to possess a Ki value for displacement of [³H]-flumazenil from the α2 and/or α3 subunit of the human GABAA receptor of 100 nM or less.

EXAMPLE 1

3-(2-Fluorophenyl)-5-(morpholin-4-yl)-[1.2.3]triazolori.5-αlquinazoline

(a) 3-(2-Fluorophenyl)-fl.2,3]triazolo[1.5-α]quinazolin-5(4H)-one Sodium metal (1.4 g, 60 mmol) was dissolved in ethanol (100 ml) at room temperature under nitrogen. 2-Fluorophenylacetonitrile (3.85 ml, 30 mmol) was added, followed by the dropwise addition of a solution of 2- azidobenzoic acid (4.71 g, 29 mmol) in ethanol (60 ml). The thick white suspension was refluxed for 18 h then cooled and poured into water (800 ml). The mixture was acidified to pΗ 3-4 with aqueous IM citric acid and the precipitated solid was collected. The solid was washed with diethyl ether (20 ml) and dried in υacuo to give 3-(2-fluorophenyl)- [l,2,3]triazolo[l,5-α]quinazolin-5(4H)-one (8.81 g, 100%), m.p. 238-241°C (DMF). Found: C, 64.33; Η, 3.06; N, 20.29. C15Η9FN4O requires C, 64.28; H, 3.24; N, 19.99%. δ_H (360 MHz; DMSO) 7.33-7.38 (2H, m), 7.46-7.55 (IH, m), 7.69-7.73 (2H, m), 8.02 (IH, ddd, = 9, 9 and 1), 8.24 (IH, dd, J = 8 and 1), 8.38 (IH, d, J = 8) and 12.40 (IH, br s); m/z (ES+) 821 (M+H⁺).

(b) 3-(2-Fluorophenyl)-5-(4-methylbenzenesulfonyloxy)- [l,2,3]triazolofl,5-α]quinazoline Triethylamine (5.6 ml, 40 mmol) was added to a stirred solution of

3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin-5(4H)-one (5.47 g, 19.5 mmol) and p-toluenesulfonyl chloride (3.82 g, 20 mmol) in dry N,N- dimethylformamide (100 ml) at room temperature under nitrogen. The brown suspension was stirred for 18 h then diluted with water (800 ml). The yellow precipitate was collected, washed sequentially with water and diethyl ether, then dried in vacuo to give 3-(2-fluorophenyl)-5-(4- methylbenzenesulfonyloxy)-[l,2,3]triazolo[l,5-α]quinazoline (8.65 g, 100%). δ_Η (400 MHz; CDC1₃) 2.42 (3H, s), 7.23 (2H, d, J = 8), 7.28-7.34 (2H, m), 7.47-7.50 (IH, m), 7.76 (IH, dd, J = 8 and 8), 7.87 (IH, ddd, J = 7, 7 and 2), 8.04-8.08 (3H, m), 8.30 (IH, dd, J = 8 and 1), 8.70 (IH, d, J = 8); m/z (ES+) 435 (M+H⁺).

(c) 3-(2-Fluorophenyl)-5-(morpholin-4-yl)-n.2.31triazolo 1.5- αlquinazoline A solution of 3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)-

[l,2,3]triazolo[l,5-α]quinazoline (0.10 g, 0.23 mmol), triethylamine (0.10 ml, 0.7 mmol) and morpholine (0.025 g, 0.25 mmol) in dry N,N- dimethylformamide (2 ml) was stirred at 50°C under nitrogen for 18 h. The mixture was cooled, then diluted with water (10 ml) and 10% methano dichloromethane (5 ml). The two phases were separated by filtration through a PTFE membrane and the organic layer was concentrated. Trituration and washing with ethyl acetate-diethyl ether gave 3-(2-fluorophenyl)-5-(morpholin-4-yl)-[l,2,3]triazolo[l,5-α]quinazoline (0.065 g, 81%). δ_H (360 MHz; DMSO) 3.61 (4H, dd, J = 5 and 5), 3.86 (4H, dd, J = 5 and 5), 7.34-7.39 (2H, m), 7.42-7.50 (IH, m), 7.77 (IH, dd, J = 7 and 7), 8.04-8.10 (2H, m), 8.22 (IH, d, J = 8), 8.59 (IH, d, J = 8); m/z (ES+) 350 (M+H⁺).

EXAMPLE 2

5-r5.6-Dihvdroimidazori,2-αlpyrazin-7(8H)-yl1-3-(2-fluorophenyl)- fl,2.3]triazolo[ .5-α1quinazoline

Prepared from 5,6,7,8-tetrahydroimidazo[l,2-α]pyrazine as described for Example 1, step c (0.020 g, 23%). δ_Η (360 MHz; CDC1₃) 4.12

(2H, dd, J = 6 and 6), 4.41 (2H, dd, J = 6 and 6), 5.02 (2H, s), 6.93 (IH, s), 7.07 (IH, s), 7.21-7.32 (2H, m), 7.36-7.40 (IH, m), 7.68 (IH, dd, J = 7 and

7), 7.95 (IH, dd, J = 7 and 7), 8.07-8.10 (2H, m), 8.73 (IH, d, J = 8); m/z

(ES+) 386 (M+H⁺).

EXAMPLE 3

5-[5-6-Dihvdroimidazori.5-α]pyrazin-7(8H)-yl]-3-(2-fluorophenyl)- [1.2.31triazolo[l,5-α]quinazoline

Prepared from 5,6,7,8-tetrahydroimidazo[l,5-α]pyrazine as described for Example 1, step c (0.033 g, 37%). δ_H (360 MHz; CDCI3) 4.07 (2H, dd, J = 6 and 6), 4.44 (2H, dd, J = 6 and 6), 4.92 (2H, s), 6.93 (IH, s), 7.22-7.32 (2H, m), 7.37-7.41 (IH, m), 7.60 (IH, s), 7.69 (IH, dd, J = 8 and 8), 7.96 (IH, dd, = 8 and 8), 8.05-8.09 (2H, m), 8.73 (IH, d, = 8); m/z (ES+) 386 (M+H⁺). EXAMPLE 4

5-r5.6-Dihvdrori.2,41triazolorL5-α]^pyrazin-7(8H)-vn-3-(2-fluorophenylV [l,2,3]triazolo[1.5-α]quinazoline Prepared from 5,6,7,8-tetrahydro[l,2,4]triazolo[l,5-α]pyrazine as described for Example 1, step c (0.047 g, 53%). Found: C, 62.52; H, 3.96; N, 29.10. C₂oHi₅FN8 requires C, 62.17; H, 3.91; N, 29.00%. δ_H (360 MHz; CDCls) 4.16 (2H, dd, J = 5 and 5), 4.61 (2H, dd, J = 5 and 5), 5.02 (2H, s), 7.22-7.33 (2H, m), 7.40-7.42 (IH, m), 7.71 (IH, dd, J = 8 and 8), 7.95-8.08 (4H, m), 8.75 (IH, ά, J = 8); m/z (ES+) 387 (M+H⁺).

EXAMPLE 5

3-(2-Fluorophenyl)-5-(3-oxo-4-phenylpiperazin-l-yl)-[l,2₁3]triazolo[l,5- αlquinazoline

Prepared from l-phenylpiperazin-2-one as described for Example 1, step c (0.054 g, 53%). δ_H (360 MHz; CDCI3) 4.03-4.06 (2H, m), 4.10-4.13 (2H, m), 4.57 (2H, s), 7.20-7.46 (8H, m), 7.68 (IH, dd, J = 8 and 8), 7.96 (IH, dd, = 8 and 8), 8.08-8.10 (2H, m), 8.73 (IH, d, J = 8); m/z (ES+) 439 (M+H⁺).

EXAMPLE 6

5-(4-Ethoxycarbonylpiperazin-l-yl)-3-(2-fluorophenyl)-[l,2,3]triazolofl,5- α]quinazoline

Prepared from ethyl 1-piperazincarboxylate as described for Example 1, step c (0.034 g, 35%). δ_H (360 MHz; CDCI3) 1.30 (3H, t, J = 7), 3.61-3.64 (4H, m), 3.75-3.77 (4H, m), 4.19 (2H, q, J = 7), 7.20-7.30 (2H, m), 7.34-7.40 (IH, m), 7.64 (IH, dd, J = 8 and 8), 7.92 (IH, dd, J = 8 and 8), 8.03 (IH, d, J = 8), 8.11 (IH, ddd, J = 8, 8 and 2), 8.72 (IH, d, J = 8); m/z (ES+) 421 (M+H⁺). EXAMPLE 7

5-(3-Ethoxycarbonylpiperidin-l-yl)-3-(2-fluorophenyl)-[l,2,3]triazolo[1.5- αl uinazoline

Prepared from ethyl 3-piperidinecarboxylate as described for Example 1, step c (0.049 g, 49%). Found: C, 65.05; H, 5.22; N, 16.07. C23H₂2FON₅.0.33(H₂O) requires C, 64.94; H, 5.37; N, 16.46%. δ_H (360 MHz; DMSO) 1.14 (3H, t, = 7), 1.70-1.90 (3H, m), 2.00-2.10 (IH, m), 2.90-3.00 (IH, m), 3.35-3.50 (2H, m), 3.85-3.95 (IH, m), 4.05-4.11 (3H, m), 7.32-7.39 (2H, m), 7.40-7.45 (IH, m), 7.78 (IH, dd, J = 8 and 8), 8.08 (IH, dd, = 8 and 8), 8.13 (IH, dd, = 8 and 8), 8.20 (IH, d, J = 8), 8.58 (IH, d, = 8); m/z (ES+) 420 (M+H⁺).

EXAMPLE 8

5-(4-Ethoxycarbonylpiperidin-l-yl)-3-(2-fluorophenvI)-[l,2,3]triazolo[1.5- αjquinazoline

Prepared from ethyl 4-piperidinecarboxylate as described for Example 1, step c (0.044 g, 44%). Found: C, 64.77; H, 5.15; N, 16.64.

C23H₂2FON5.0.33(H₂O) requires C, 64.94; H, 5.37; N, 16.46%. δ_H (360 MHz; DMSO) 1.21 (3H, t, J = 7), 1.85-2.10 (4H, m), 2.65-2.75 (IH, m), 3.15-3.30 (2H, m), 4.00-4.15 (4H, m), 7.30-7.40 (2H, m), 7.42-7.50 (IH, m), 7.77 (IH, dd, = 8 and 8), 8.03-8.12 (2H, m), 8.17 (IH, d, J = 8), 8.58 (IH, d, J = 8); m/z (ES+) 420 (M+H⁺). EXAMPLE 9

3-(2-Fluorophenyl)-5-(4-hvdroxypiperidin-l-yl)- l,2,3]triazolo[l,5- αlquinazoline

Prepared from 4-hydroxypiperidine as described for Example 1, step c (0.050 g, 58%). δ_H (360 MHz; DMSO) 1.60-1.75 (2H, m), 1.90-2.05 (2H, m), 3.30-3.40 (2H, m), 3.79-3.82 (IH, m), 3.85-3.95 (2H, m), 4.80 (IH, d, J = 4), 7.34-7.44 (3H, m), 7.77 (IH, dd, J = 8 and 8), 8.05 (IH, dd, J = 8 and 8), 8.12-8.16 (2H, m), 8.57 (IH, d, J = 8); m/z (ES+) 364 (M+H⁺).

EXAMPLE 10

3-(2-Fluorophenyl)-5-|i4-(pyridin-4-yl)piperazin-l-yl1-[l,2,31triazolo[1.5- α]quinazoline Prepared from l-(pyridin-4-yl)piperazine as described for Example

1, step c (0.067 g, 66%). δ_H (400 MHz; DMSO) 3.72-3.75 (4H, m), 3.80-3.83 (4H, m), 6.97-7.00 (2H, d, J = 7), 7.35-7.40 (2H, m), 7.45-7.48 (IH, ), 7.80 (IH, dd, J = 7 and 7), 8.09-8.11 (2H, m), 8.23 (2H, d, J = 7), 8.28 (IH, d, = 7), 8.61 (IH, d, J = 7); m/z (ES+) 426 (M+H⁺).

EXAMPLE 11

3-(2-Fluorophenyl)-5-[4-(pyridin-2-yl)piperazin-l-yl]-ri,2,3]triazolo l,5- αlquinazoline Prepared from l-(pyridin-2-yl)piperazine as described for Example

1, step c (0.069 g, 68%). δ_H (360 MHz; DMSO) 3.75-3.80 (8H, m), 6.69 (IH, dd, = 7 and 6), 6.90 (IH, d, J = 7), 7.35-7.50 (3H, m), 7.58 (IH, dd, = 7 and 7), 7.80 (IH, dd, = 8 and 8), 8.08-8.16 (3H, m), 8.29 (IH, d, J = 8), 8.60 (IH, d, = 7); m/z (ES+) 426 (M+H⁺). EXAMPLE 12

5-(4-Acetylpiperazin-l-yl)-3-(2-fluorophenyl)-ri,2,31triazolo l,5- α]quinazoline Prepared from 1-acetylpiperazine as described for Example 1, step c

(0.068 g, 73%). Found: C, 64.61; H, 4.91; N, 21.53. C₂ιHi9FN6.0.1(H₂O) requires C, 64.31; H, 4.93; N, 21.43%. δ_H (360 MHz; DMSO) 2.07 (3H, s), 3.61-3.67 (4H, m), 3.71-3.74 (4H, m), 7.35-7.40 (2H, m), 7.42-7.50 (IH, m), 7.79 (IH, dd, J = 7 and 7), 8.06-8.13 (2H, m), 8.24 (IH, d, J = 7), 8.60 (IH, d, J = 7); m/z (ES+) 391 (M+H⁺).

EXAMPLE 13

3-(2-Fluorophenyl)-5-[2-oxopiperazin-4(lH)-yll-ri.2,31triazolon.5- αlquinazoline

Prepared from piperazin-2(lH)-one as described for Example 1, step c (0.031 g, 36%). Found: C, 62.09; Η, 4.01; N, 22.53. C₁₉Ηi5FNGθ.0.33(Η2θ) requires C, 61.96; H, 4.29; N, 22.82%. δ_H (360 MHz; DMSO) 3.45-3.55 (2H, m), 3.85-3.90 (2H, m), 4.19 (2H, s), 7.35-7.40 (2H, m), 7.44-7.46 (IH, m), 7.78 (IH, dd, J = 7 and 7), 8.06-8.14 (3H, m), 8.24 (IH, d, J = 7), 8.61 (IH, d, J = 8); m/z (ES+) 363 (M+H⁺).

EXAMPLE 14

3-(2-Fluorophenyl)-5-(l-methyl-2-oxopiperazin-4-yl)-[l,2,31triazolo[l,5- α]quinazoline

Prepared from l-methylpiperazin-2(lH)-one as described for

Example 1, step c (0.033 g, 73%). δ_Η (360 MHz; DMSO) 2.91 (3H, s), 3.61

(2H, dd, J = 6 and 6), 3.96 (2H, dd, J = 6 and 6), 4.24 (2H, s), 7.35-7.40 (2H, m), 7.44-7.46 (IH, m), 7.78 (IH, dd, J = 7 and 7), 8.06-8.12 (2H, m),

8.23 (IH, d, J = 7), 8.59 (IH, d, J = 7); m/z (ES+) 377 (M+H⁺). EXAMPLE 15

5-[5,6-Dihvdroimidazo[1.2-α1pyrazin-7(8H)-vn-7-fluoro-3-(2-fluorophenyl)- [l-2.3ltriazolo[l,5-α]quinazoline

(a) 7-Fluoro-3-(2-fluorophenyl)-ri.2.31triazolo[1.5-α]quinazolin-5(47J)- one

Prepared from 2-azido-5-fluorobenzoic acid as described for Example 1, step a (1.57 g, 100%). δ_Η (360 MHz; DMSO) 7.32-7.37 (2H, m), 7.44-7.50 (IH, m), 7.83-7.89 (2H, m), 7.93 (IH, dd, J = 9 and 3), 8.42 (IH, dd, J = 9 and 5), 12.60 (IH, br s); m/z (ES+) 299 (M+H₂0+H⁺).

(b) 7-Fluoro-3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)- ri.2,31triazolofl,5-α]quinazoline

Prepared from 7-fluoro-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- α]quinazolin-5(4H)-one as described for Example 1, step b (0.259 g, 80%). δ_Η (360 MHz; CDC1₃) 2.42 (3H, s), 7.22-7.35 (4H, m), 7.46-7.50 (IH, m), 7.76-7.81 (IH, m), 7.87 (IH, dd, J = 7 and 7), 7.94 (IH, dd, J = 8 and 2), 8.06 (2H, d, = 7), 8.71 (IH, dd, J = 8 and 5); m/z (ES+) 453 (M+H⁺).

(c) 5-r5.6-Dihvdroimidazori.2-αlpyrazin-7(8H)-yll-7-fluoro-3-(2- fluorophenvD- [1.2.31 triazolo [1.5-α] q uinazoline

Prepared from 5,6,7,8-tetrahydroimidazo[l,2-α]pyrazine and 7- fluoro-3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)-

[l,2,3]triazolo[l,5-α]quinazoline as described for Example 1, step c (0.031 g, 26%). Found: C, 61.72; Η, 3.79; N, 23.14. C2iΗ,₅F₂N7.0.33(Η2θ) requires C, 61.65; H, 3.86; N, 23.96%. δ_H (360 MHz; CDCI3) 4.09 (2H, dd, = 5 and 5), 4.05 (2H, dd, = 5 and 5), 4.97 (2H, s), 6.93 (IH, d, J = 1), 7.07 (IH, d, J = 1), 7.21-7.32 (2H, m), 7.37-7.40 (IH, m), 7.67-7.74 (2H, m), 8.06 (IH, ddd, J = 7, 7 and 2), 8.75 (IH, dd, J = 8 and 5); m/z (ES+) 404 (M+H⁺). EXAMPLE 16

5-[Bis(2-methoxyethyl)amino]-3-(2-fluorophenyl)-[l,2,3]triazolo[1.5- α]quinazoline

Prepared from bis(2-methoxyethyl)amine as described for Example 1, step c (0.015 g, 17%). δ_H (360 MHz; CDC1₃) 3.39 (6H, s), 3.77 (4H, t, J = 6), 3.89 (4H, t, = 6), 7.18-7.28 (2H, m), 7.30-7.40 (IH, m), 7.60 (IH, dd, J = 8 and 8), 7.87 (IH, dd, J= 8 and 8), 8.11 (IH, ddd, = 8, 8 and 2), 8.43 (IH, dd, = 8 and 1), 8.67 (IH, d, J = 8); m/z (ES+) 396 (M+H⁺).

EXAMPLE 17

3-(2-Fluorophenyl)-5-(thiomorpholin-4-yl)-[l,2.31triazolo[l,5-α]quinazoline Prepared from thiomorpholine as described for Example 1, step c

(0.060 g, 71%). Found: C, 61.82; H, 4.55; N, 18.48. d9Hi6N₅SF.0.33(H2θ) requires C, 61.44; H, 4.52; N, 18.85%. δ_H (360 MHz; DMSO) 2.90-2.93 (4H, m), 3.85-3.88 (4H, m), 7.35-7.40 (2H, m), 7.43-7.47 (IH, m), 7.77 (IH, dd, J = 8 and 8), 8.04-8.12 (2H, m), 8.15 (IH, d, J = 8), 8.58 (IH, d, J = 8); m/z (ES+) 366 (M+H⁺).

EXAMPLE 18

5-[4-(Dimethylamino)piperidin-l-yl1-3-(2-fluorophenyl)-ri,2.3]triazolo[l,5- α]quinazoline

Prepared from 4-(dimethylamino)piperidine as described for Example 1, step c (0.059 g, 66%). δ_H (360 MHz; DMSO) 1.65-1.80 (2H, m), 1.90-2.00 (2H, m), 2.25 (6H, s), 2.40-2.50 (IH, m), 3.11 (2H, broad dd, J = 12 and 12), 4.14 (2H, broad d, J = 13), 7.34-7.39 (2H, m), 7.40-7.48 (IH, m), 7.77 (IH, dd, J = 7 and 7), 8.03-8.17 (3H, m), 8.56 (IH, d, J = 8); m/z (ES+) 391 (M+H⁺). EXAMPLE 19

3-(2-Fluorophenyl)-5-[4-(pyrrolidin-l-yl)piperidin-l-yl]-[l,2,3]triazolo[1.5- α]quinazoline

Prepared from 4-(pyrrolidin-l-yl)piperidine as described for Example 1, step c (0.062 g, 65%). δ_H (360 MHz; DMSO) 1.60-1.70 (6H, m), 1.98-2.08 (2H, m), 2.25-2.35 (IH, m), 3.20 (2H, broad dd, J = 12 and 12), 4.05 (2H, broad d, J = 13), 7.33-7.39 (2H, m), 7.40-7.48 (IH, m), 7.76 (IH, dd, J = 8 and 8), 8.05 (IH, dd, J = 7 and 7), 8.10-8.16 (2H, m), 8.56 (IH, d, J = 8); m/z (ES+) 417 (M+H⁺).

EXAMPLE 20

3-(2-Fluorophenyl)-5-[4-(piperidin-l-yl)piperidin-l-yl1-ri,2,31triazolo[1.5- α]quinazoline

Prepared from 4-(piperidin-l-yl)piperidine as described for Example

1, step c (0.084 g, 85%). Found: C, 67.42; H, 6.23; N, 18.38.

C₂5H₂7N₆F.0.9(H₂O) requires C, 67.22; H, 6.50; N, 18.81%. δ_H (360 MHz; DMSO) 1.35-1.55 (6H, m), 1.70-1.82 (2H, m), 1.85-1.95 (2H, m), 2.45-2.60

(5H, m, partly obscured by DMSO peak), 3.08 (2H, broad dd, J = 12 and

12), 4.15 (2H, broad d, J = 13), 7.34-7.39 (2H, m), 7.41-7.46 (IH, m), 7.76

(IH, dd, J = 8 and 8), 8.02-8.17 (3H, m), 8.56 (IH, d, J = 8); m/z (ES+) 431

(M+H⁺).

EXAMPLE 21

5-[Bis(2-hydroxyethyl)amino]-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- α]quinazoline Prepared from bis(2-hydroxyethyl)amine as described for Example

1, step c (0.053 g, 30%). δ_H (400 MHz; DMSO) 3.78-3.82 (8H, m), 4.85 (2H, t, J = 5), 7.32-7.37 (2H, m), 7.40-7.45 (IH, m), 7.74 (IH, ddd, J = 7, 7 and 1), 8.02 (IH, dd, J = 7 and 7), 8.10 (IH, ddd, J = 7 and 7), 8.43 (IH, dd, J = 8 and 1), 8.56 (IH, d, = 7); wi β (ES+) 368 (M+H⁺).

EXAMPLE 22

3-(2-Fluorophenyl)-5-(4-oxopiperidin-l-yl)-[l,2,3]triazolo[l,5-αlquinazoline

A solution of 3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)- [l,2,3]triazolo[l,5-α]quinazoline (Example 1, step b) (3.0 g, 6.91 mmol), 4- piperidone monohydrate, hydrochloride salt (1.28 g, 8.3 mmol) and triethylamine (3.0 ml, 21 mmol) in dry N,N-dimethylformamide (25 ml) was stirred at 60°C under nitrogen for 4 h. The mixture was diluted with water (100 ml) and extracted with 10% methanokdichloromethane (150 ml). The extract was dried (Na2S0 ), filtered and concentrated. The residual solid was washed with diethyl ether-ethyl acetate and dried in vacuo to give 3-(2-fluorophenyl)-5-(4-oxopiperidin-l-yl)-[l,2,3]triazolo[l,5- α]quinazoline (1.90 g, 76%). δ_H (360 MHz; DMSO) 2.67 (4H, t, J = 6), 3.99 (4H, t, J = 6), 7.33-7.48 (3H, m), 7.78 (IH, dd, J = 7 and 7), 8.05-8.11 (2H, m), 8.25 (IH, d, J = 8), 8.58 (IH, d, J = 8); m/z (ES+) 362 (M+H⁺).

EXAMPLE 23

5-(l-Ethyl-2-oxopiperazin-4-yl)-3-(2-fluorophenyl)-[1.2.31triazolori,5- alquinazoline Sodium hydride (55% w/w in oil; 0.02 g, 0.46 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-5-(2-oxopiperazin-4(lH)-yl)- [l,2,3]triazolo[l,5-α]quinazoline (0.1 g, 0.28 mmol) (Example 13) and iodoethane (0.15 ml) in V,N-dimethylformamide. The mixture was stirred at 50°C for 3 h, then cooled and diluted with water (8 ml) and 10% methanokdichloromethane (10 ml). The two phases were separated by filtration through a teflon membrane and the organic layer was concentrated. Preparative thin layer chromatography on silica, eluting with 5% methanol-dichloromethane, gave 5-(l-ethyl-2-oxopiperazin-4-yl)- 3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazoline (0.035 g, 32%). δ_H (360 MHz; CDCls) 1.20 (3H, t, J = 7), 3.52 (2H, q, J = 7), 3.67 (2H, dd, = 6 and 6), 3.96 (2H, dd, J = 6 and 6), 4.38 (2H, s), 7.20-7.32 (2H, m), 7.35-7.42 (IH, m), 7.65 (IH, dd, J = 7 and 7), 7.94 (IH, dd, J = 7 and 7), 8.02 (IH, d, J= 7), 8.23 (IH, dd, J= 7 and 7), 8.72 (IH, ά, J = 7); m/z (ES+) 391 (M+H⁺).

EXAMPLE 24

3-(2-Fluorophenyl)-5-(2-oxo-l-propylpiperazin-4-yl)- l,2,3]triazolori.5- α]quinazoline

Prepared from iodopropane as for Example 23 to give the title compound (0.046 g, 41%). δ_H (360 MHz; CDCI3) 0.93 (3H, t, J = 7), 1.61 (2H, tq, J = 7 and 7), 3.43 (2H, t, J = 7), 3.66 (2H, dd, J = 6 and 6), 3.96 (2H, dd, J = 6 and 6), 4.38 (2H, s), 7.20-7.30 (2H, m), 7.35-7.39 (IH, m), 7.65 (IH, dd, J = 7 and 7), 7.94 (IH, dd, J = 7 and 7), 8.02 (IH, d, J = 7), 8.23 (IH, dd, J = 7 and 7), 8.72 (IH, d, J = 7); m/z (ES+) 405 (M+H⁺).

EXAMPLE 25

3-(2-Fluorophenyl)-5-f2-oxo-l-(2-propenyl)piperazin-4-yll-[1.2.31triazolo- [l,5-α]quinazoline Prepared from l-bromoprop-2-ene as for Example 23 to give the title compound (0.027 g, 24%). δ_H (360 MHz; CDCI3) 3.63 (2H, dd, J = 6 and 6), 3.95 (2H, dd, = 6 and 6), 4.10 (2H, d, J = 5), 4.40 (2H, s), 5.21-5.26 (2H, m), 5.75-5.85 (IH, m), 7.20-7.30 (2H, m), 7.35-7.39 (IH, m), 7.65 (IH, dd, J = 7 and 7), 7.94 (IH, dd, J= 7 and 7), 8.02 (IH, d, J = l), 8.10 (IH, dd, J = 7 and 7), 8.72 (IH, d, «_/ = 7); m/z (ES+) 403 (M+H⁺). EXAMPLE 26

3-(2-Fluorophenyl)-5-(4-hydroxy-4-methylpiperidin-l-yl)-[l,2,31triazolo- [l,5-α]quinazoline Methylmagnesium bromide (3M in diethyl ether, 0.24 ml, 0.72 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-5-(4- oxopiperidin-l-yl)-[l,2,3]triazolo[l,5-α]quinazoline (Example 22) (0.107 g, 0.3 mmol) in dry tetrahydrofuran (2 ml) at room temperature under nitrogen. After stirring for 2 h, the mixture was diluted with water (20 ml) and IM aqueous citric acid (5 ml). The mixture was extracted with dichloromethane (20 ml) and the organic extract was dried (Na2S0 ), filtered and concentrated. Preparative thin layer chromatography on silica, eluting with 2% methanol: dichloromethane, gave 3-(2-fluorophenyl)- 5-(4-hydroxy-4-methylpiperidin-l-yl)-[l,2,3]triazolo[l,5-α]quinazoline (0.053 g, 47%). δ_H (360 MHz; CDC1₃) 1.38 (3H, s), 1.75-1.85 (2H, m), 1.90- 2.00 (2H, m), 3.56-3.64 (2H, m), 3.83-3.89 (2H, m), 7.20-7.30 (2H, m), 7.30- 7.40 (IH, m), 7.60 (IH, dd, J = 7 and 7), 7.88 (IH, dd, = 7 and 7), 8.02 (IH, d, J = 7), 8.15 (IH, dd, J = 7 and 7), 8.68 (IH, d, J = 7); m/z (ES+) 378 (M+H⁺).

EXAMPLE 27

l-{4-[3-(2-Fluorophenyl)-[l,2,3]triazolo[l,5-αlquinazolin-5-yl]piperazin-l- yllpropan-1-one δ_H (400 MHz; CDCI3) 1.20 (3H, t, J = 7.4), 2.43 (2H, q, J = 7.4), 3.62-

3.69 (4H, br m), 3.73-3.79 (2H, br m), 3.88-3.93 (2H, br m), 7.20-7.30 (2H, m), 7.35-7.41 (IH, m), 7.63-7.67 (IH, m), 7.91-7.95 (IH, m), 8.03-8.12 (2H, m), 8.71-8.73 (IH, ); m/z (ES+) 405 (M+H⁺). EXAMPLE 28

2,2-Dimeth^yl-l-{4-[3-(2-fluoro^phenyl)-[l,2,31triazolo[l,5-α]quinazolin-5- yl]piperazin-l-yl)propan-l-one δ_H (400 MHz; DMSO) 1.24 (9H, s), 3.61-3.67 (4H, br m), 3.80-3.87

(4H, br m), 7.35-7.39 (2H, m), 7.42-7.48 (IH, m), 7.76-7.80 (IH, m), 8.06- 8.11 (2H, m), 8.24-8.25 (IH, m), 8.58-8.60 (IH, m); m/z (ES+) 433 (M+H+).

EXAMPLE 29

/V-r3-(2-Fluorophenyl)-ri.2,31triazolori.5-αlquinazolin-5-yl1-A^r-methyl-/V-d- methylpiperidin-4-yl)amine

Prepared from N-methyl-N-(l-methylpiperidin-4-yl)amine as described for Example 1, step c (0.050 g, 56%). δ_H (400 MHz; CDC1₃) 1.96- 2.13 (6H, broad m), 2.32 (3H, s), 2.98-3.01 (2H, broad m), 3.20 (3H, s),

4.17-4.20 (IH, broad m), 6.01-6.04 (IH, broad m), 7.19-7.27 (2H, m), 7.30-

7.35 (IH, m), 7.59 (IH, ddd, J = 7, 7 and 1), 7.87 (IH, ddd, J = 7, 7 and 1),

8.04 (IH, d, J = 8), 8.19 (IH, ddd, J = 8, 8 and 2), 8.69 (IH, d, J = 8); m/z

(ES+) 391 (M+H⁺).

EXAMPLE 30

l-[3-(2-Fluorophenyl)-fl,2,3]triazolo 1.5-α1quinazolin-5-yl]-[l,41diazepan-5- one Prepared from [l,4]diazepan-5-one as described for Example 1, step c (0.065 g, 75%). δ_H (400 MHz; CDCI3) 2.95-2.99 (2H, m), 3.58-3.62 (2H, ), 3.85-3.88 (4H, m), 6.01-6.04 (IH, broad m), 7.19-7.30 (2H, m), 7.35-7.41 (IH, m), 7.65 (IH, ddd, = 7, 7 and 1), 7.93 (IH, ddd, J = 7, 7 and 1), 7.96 (IH, d, J = 8), 8.08 (IH, ddd, J = 8, 8 and 2), 8.73 (IH, d, J = 8); m/z (ES+) 371 (M+H⁺). EXAMPLE 31

3-(2-Fluorophenyl)-5-(piperidin-l-yl)-[l,2,31triazolo[l,5-α]quinazoline

Prepared from piperidine as described for Example 1, step c (0.030 g, 38%). δ_H (400 MHz; CDC1₃) 1.65-1.79 (2H, m), 1.82-1.91 (4H, m), 3.59 (4H, m), 7.19-7.30 (2H, m), 7.31-7.38 (IH, m), 7.60 (IH, ddd, = 7, 7 and 1), 7.86 (IH, ddd, J = 7, 7 and 1), 8.01 (IH, dd, J = 8 and 1), 8.17 (IH, ddd, c/ = 8, 8 and 2), 8.67 (IH, dd, J = 8 and 1); m/z (ES+) 348 (M+H⁺).

EXAMPLE 32

3-(2-Fluorophenyl)-5-[4-(morpholin-4-yl)piperidin-l-yl1-[l,2.3]triazolo l,5- α]quinazoline

Sodium triacetoxyborohydride (0.53 g, 2.75 mmol) was added portionwise over 10 min to a solution of 3-(2-fluorophenyl)-5-(4- oxopiperidin-l-yl)-[l,2,3]triazolo[l,5-α]quinazoline (0.30 g, 0.83 mmol) and morpholine (0.36 g, 4.1 mmol) in CH2CI2 (5 ml) and the mixture was allowed to stir for a further 48 h. The mixture was diluted with CH2CI2 (150 ml), washed with water (50 ml) and brine (50 ml), dried over MgS0 and evaporated to give a yellow oil. Purification by flash column chromatography on silica eluting with CH2Cl2:MeOH (98:2) followed by trituration with diethyl ether gave 3-(2-fluorophenyl)-5-[4-(morpholin-4- yl)piperidin-l-yl]-[l,2,3]triazolo[l,5-α]quinazoline (0.255 g, 71%) as a white solid. δ_H (400 MHz; CDCI3) 1.78-1.88 (2H, m), 2.04-2.08 (2H, m), 2.43-2.53 (IH, m), 2.58-2.68 (4H, m), 3.07-3.14 (2H, m), 3.75-3.78 (4H, m), 4.17-4.22 (2H, m), 7.19-7.30 (2H, m), 7.33-7.39 (IH, m), 7.61 (IH, ddd, = 8, 8 and 1), 7.88 (IH, ddd, J = 8, 8 and 1), 8.00 (IH, d, = 8), 8.13 (IH, ddd, J = 7, 7 and 2), 8.69 (IH, d, = 8); m/z (ES+) 433 (M+H⁺). EXAMPLE 33

4-(2-Dimethylaminoethyl)-l-[3-(2-fluorophenvD-[1.2.31triazolon.5- α1quinazolin-5-yl1-[l,4]diazepan-5-one Prepared from 4-(2-dimethylaminoethyl)-[l,4]diazepan-5-one as described for Example 1, step c (0.035 g, 34%). δ_H (360 MHz; CDC1₃) 2.25 (6H, s), 2.46 (2H, dd, J = 7 and 7), 2.98-3.02 (2H, m), 3.56 (2H, dd, J = 7 and 7), 3.73-3.88 (6H, m), 7.19-7.31 (2H, m), 7.35-7.39 (IH, m), 7.64 (IH, ddd, J = 7, 7 and 1), 7.92 (IH, ddd, = 7, 7 and 1), 7.96 (IH, dd, = 8 and 1), 8.10 (IH, ddd, = 7, 7 and 2), 8.72 (IH, d, J = 8); m/z (ES+) 448 (M+H⁺).

EXAMPLE 34

l'-r3-(2-Fluorophenyl)-[l,2,3Uriazolofl.5-αlquinazolm-5-yll- [1.4']bipiperidinyl-4-carboxylic acid ethyl ester: oxalate salt

Prepared from [l,4']bipiperidinyl-4-carboxylic acid ethyl ester as described for Example 1, step c (0.067 g, 49%). δ_H (400 MHz; DMSO) 1.19 (3H, t, J = 7), 1.70-2.15 (8H, m), 2.55-2.68 (IH, m), 2.90-3.07 (2H, m), 3.12- 3.19 (2H, m), 3.30-3.40 (3H, m), 4.08 (2H, q, J = 7), 4.22-4.26 (2H, m), 7.34- 7.40 (2H, m), 7.43-7.49 (IH, m), 7.78 (IH, ddd, J = 8, 8 and 1), 8.05-8.11 (2H, m), 8.17 (IH, d, J = 8), 8.17 (IH, dd, J = 8 and 1); m/z (ES+) 503 (M+H⁺).

EXAMPLE 35

5-[4-(3,4-Dihvdro-lH-isoquinolin-2-yl)piperidin-l-yll-3-(2-fluorophenyl)- [l,2,31triazolo[l,5-α1quinazoline

Prepared from 2-(piperidin-4-yl)-l,2,3,4-tetrahydroisoquinoline as described for Example 1, step c (0.039 g, 35%). δ_H (400 MHz; CDCI₃) 1.92- 2.15 (4H, m), 2.76-2.94 (5H, m), 3.11-3.17 (2H, m), 3.87 (2H, s), 4.22-4.27 (2H, m), 7.03-7.30 (6H, m), 7.33-7.39 (IH, m), 7.62 (IH, ddd, J = 8, 8 and 1), 7.89 (IH, ddd, J = 8, 8 and 1), 8.03 (IH, dd, J = 8 and 1), 8.15 (IH, ddd, J = 8, 8 and 1), 8.69 (IH, dd, J = 8 and 1); m/z (ES+) 479 (M+H⁺).

EXAMPLE 36

l-(l- 3-(2-Fluorophenyl)-[l,2,31triazolo[l,5-αlquinazolin-5-yl1piperidin-4- yli-[l,4]diazepan-5-one

Prepared from l-(piperidin-4-yl)-[l,4]diazepan-5-one as described for Example 1, step c (0.063 g, 60%). δ_H (400 MHz; CDC1₃) 1.82-1.95 (4H, m), 2.65-2.68 (2H, m), 2.76-2.85 (5H, m), 3.03-3.11 (2H, m), 3.31-3.35 (2H, m), 4.20-4.24 (2H, m), 5.87-5.91 (IH, broad m), 7.20-7.30 (2H, m), 7.31-7.40 (IH, m), 7.63 (IH, ddd, J = 7, 7 and 1), 7.90 (IH, ddd, J = 7, 7 and 1), 7.96 (IH, dd, J = 7 and 1), 8.03 (IH, ddd, J = 8, 8 and 2), 8.69 (IH, dd, J = 8 and 1); m/z (ES+) 460 (M+H⁺).

EXAMPLE 37

N.N-Dimethyl-7V-{l-[3-(2-fluorophenyl)-fl,2.31triazolon.5-α1quinazolin-5- vI|pyrrolidin-3-yl}amine: oxalate salt

Prepared from N,N-dimethyl-iV-(pyrrolidin-3-yl)amine as described for Example 1, step c (0.044 g, 41%). δ_H (400 MHz; DMSO) 2.14-2.19 (IH, m), 2.32-2.42 (IH, m), 2.70 (6H, s), 3.60-3.68 (IH, m), 3.98-4.12 (3H, m), 4.21-4.26 (IH, m), 7.31-7.42 (3H, m), 7.74 (IH, ddd, J = 8, 8 and 1), 8.05 (IH, ddd, J = 8, 8 and 1), 8.17 (IH, ddd, J = 7, 7 and 1), 8.48 (IH, ά, J = 8), 8.58 (IH, dd, J = 8 and 1); m/z (ES+) 377 (M+H⁺).

EXAMPLE 38

3-(2-Fluorophenyl)-5-{4-[2-(pyrrolidin-l-yl)ethyl1piperazin-l-yl|- [l,2,3]triazolo[l,5-αlquinazoline: oxalate salt (a) 4-[3-(2-Fluorophenyl)-[l,2,31triazolo[l,5-αlquinazolin-5- yllpiperazine-1-carboxylic acid tert-hutyl ester

A solution of 3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)- [l,2,3]triazolo[l,5-α]quinazoline (0.33 g, 0.71 mmol), triethylamine (0.3 ml, 2.1 mmol) and piperazine-1 -carboxy lie acid tert-butyl ester (0.26 g, 1.4 mmol) in dry N,N-dimethylformamide (6 ml) was stirred at 50°C under nitrogen for 18 h. The mixture was cooled, then diluted with water (30 ml) and extracted with EtOAc (2 x 75 ml). The combined organic extracts were washed with brine, dried over MgS0 and evaporated to give a brown oil. Purification by flash column chromatography eluting with CH₂Cl₂:MeOH (93:7) gave 4-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- α]quinazolin-5-yl]piperazine-l-carboxylic acid tert-butyl ester as a white solid (0.28 g, 88%). δ_H (400 MHz; CDC1 ) 1.50 (9H, s), 3.59-3.62 (4H, m), 3.69-3.72 (4H, m), 7.19-7.30 (2H, m), 7.32-7.37 (IH, m), 7.63 (IH, ddd, J = 8, 8 and 1), 7.91 (IH, ddd, J = 8, 8 and 1), 8.02 (IH, d, J = 8), 8.11 (IH, ddd, J = 7, 7 and 2), 8.70 (IH, dd, = 8 and 1).

(b) 3-(2-Fluorophenyl)-5-(piperazin-l-yl)-[l,2.3]triazolofl,5- αlquinazoline: hydrochloride salt

4-[3-(2-Fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin-5- yl]piperazine-l-carboxylic acid teri-butyl ester (0.28 g, 0.63 mmol) was dissolved in dichloromethane (5 ml) and hydrogen chloride bubbled through the reaction (2 x 10 min). The precipitate was filtered and washed with diethyl ether to give 3-(2-fluorophenyl)-5-(piperazin-l-yι)-

[l,2,3]triazolo[l,5-α]quinazoline as a white solid (0.24 g, 100%). HCl salt: δ_H (360 MHz; DMSO) 3.30-3.41 (4H, m), 3.79-3.83 (4H, m), 7.35-7.41 (2H, m), 7.44-7.51 (IH, m), 7.78 (IH, ddd, J = 8, 8 and 1), 8.05-8.12 (2H, m), 8.27 (IH, d, J = 8), 8.62 (IH, dd, J= 8 and 1); m/z (ES+) 349 (M+H⁺). (c) 3-(2-Fluorophenyl)-5-{4-[2-(pyrrolidin-l-yl)ethvnpiperazin-l-yl}- [l,2,31triazolo[l,5-α1quinazoline

3-(2-Fluorophenyl)-5-(piperazin-l-yι)-[l,2,3]triazolo[l,5- αjquinazoline (0.10 g, 0.26 mmol), l-(2-chloroethyl)pyrrolidine hydrochloride (0.088 g, 0.52 mmol) and triethylamine (0.18 ml, 1.3 mmol) were dissolved in NN-dimethylformamide (4 ml) and stirred at 80°C under nitrogen for 18 h. The mixture was cooled, then diluted with water (20 ml) and extracted with CH2CI2 (2 x 50 ml). The combined organics were washed with brine (20 ml), dried over MgS0 and evaporated to give a brown oil. Purification by preparative thin layer chromatography eluting with CH₂Cl2:MeOH:NH₃(c) (92:8:0.8) gave 3-(2-fluorophenyl)-5-{4- [2-(pyrrolidin-l-yl)ethyl]piperazin-l-yl}-[l,2,3]triazolo[l,5-α]quinazoline as a white solid (0.055 g, 47%). Oxalate salt (EtOH): δ_H (400 MHz; DMSO) 1.87-1.98 (4H, m), 2.49-2.52 (6H, m, partly obscured by DMSO peak), 2.66- 2.78 (6H, m), 3.30-3.35 (2H, m, partly obscured by H₂0 peak), 3.60-3.72 (2H, m), 7.33-7.39 (2H, m), 7.43-7.49 (IH, m), 7.77 (IH, ddd, J = 8, 8 and 1), 8.05-8.13 (2H, m), 8.19 (IH, d, J = 8), 8.59 (IH, dd, J= 8 and 1); m/z (ES+) 446 (M+H⁺).

EXAMPLE 39

3-(2-Fluorophenyl)-5-(4-methoxypiperidin-l-yl)-[l,2,31triazolo[l,5- αlquinazoline

Sodium hydride (60% dispersion in oil) (0.044 g, 1.10 mmol) was added to a solution of 3-(2-fluorophenyl)-5-(4-hydroxypiperidin-l-yl)-

[l,2,3]triazolo[l,5-α]quinazoline (Example 9) (0.10 g, 0.27 mmol) in N,N- dimethylacetamide (4 ml). The mixture was stirred for 30 min before addition of methyl iodide (0.17 ml, 2.8 mmol) and then stirred for a further 18 h. The mixture was diluted with water (20 ml) and extracted with CH2CI2 (2 x 50 ml). The combined organic extracts were washed with brine (20 ml), dried over MgSO and evaporated to give a colourless oil. Purification by preparative thin layer chromatography eluting with CH₂Cl₂:MeOH:NH3(c) (95:5:0.5) gave 3-(2-fluorophenyl)-5-(4- methoxypiperidin-l-yl)-[l,2,3]triazolo[l,5-α]quinazoline (0.067 g, 65%) as a yellow solid. δ_H (360 MHz; CDC1₃) 1.84-1.90 (2H, m), 2.11-2.16 (2H, m), 3.36-3.41 (2H, m), 3.42 (3H, s), 3.51-3.54 (IH, m), 3.88-3.95 (2H, m), 7.19- 7.29 (2H, m), 7.32-7.37 (IH, m), 7.60 (IH, ddd, J = 8, 8 and 1), 7.88 (IH, ddd, J = 8, 8 and 1), 8.01 (IH, d, J = 8), 8.15 (IH, ddd, J = 7, 7 and 2), 8.67 (IH, dd, = 8 and 1); m/z (ES+) 378 (M+H⁺).

EXAMPLE 40

l-Cvclopropylmethyl-4-[3-(2-fluorophenyl)-[l,2,31triazolori₁5-αlquinazolin- 5-yI]piperazin-2-one

Sodium hydride (60% dispersion in oil) (0.40 g, 10.0 mmol) was added portionwise over 10 min to a solution of 3-oxopiperazine-l- carboxylic acid terf-butyl ester (1.00 g, 5.0 mmol) in N,N- dimethylacetamide (10 ml). The mixture was stirred for 30 min before addition of bromomethylcyclopropane (1.45 ml, 15.0 mmol) and then stirred for a further 18 h. The mixture was diluted with water (100 ml) and extracted with EtOAc (2 x 100 ml). The combined organic extracts were washed with brine (50 ml), dried over MgS0 and evaporated to give 4-cyclopropylmethyl-3-oxopiperazine-l-carboxylic acid teri-butyl ester (1.27 g, 100%) as a yellow oil. This oil was dissolved in dichloromethane and hydrogen chloride bubbled through the reaction (2 x 10 min). The solvent was evaporated to give l-cyclopropylmethylpiperazin-2-one.HCl (0.95 g, 100%) as a white solid.

A solution of 3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)- [l,2,3]triazolo[l,5-α]quinazoline (0.10 g, 0.23 mmol), triethylamine (1 ml, 7.2 mmol) and l-cyclopropylmethylpiperazin-2-one.HCl (0.22 g, 1.15 mmol) in dry iV,N-dimethylformamide (2 ml) was stirred at 50°C under nitrogen for 18 h. The mixture was cooled, then diluted with water (15 ml) and extracted with EtOAc (2 x 75 ml). The combined organic extracts were washed with brine, dried over MgS0 and evaporated to give a brown oil. Purification by preparative thin layer chromatography eluting with CH₂Cl₂:MeOH (93:7) gave l-cyclopropylmethyl-4-[3-(2-fluorophenyl)- [l,2,3]triazolo[l,5-α]quinazolin-5-yl]piperazin-2-one (0.020 g, 21%) as a white solid. δ_H (400 MHz; CDC1₃) 0.26-0.31 (2H, m), 0.52-0.58 (2H, m), 0.99-1.05 (IH, m), 3.37 (2H, d, = 7), 3.77 (2H, dd, J = 5 and 5), 3.97 (2H, dd, = 5 and 5), 4.39 (2H, s), 7.20-7.31 (2H, m), 7.35-7.41 (IH, m), 7.66 (IH, dd, J = 7 and 7), 7.94 (IH, dd, J = 8 and 8), 8.02-8.11 (2H, m), 8.72 (IH, d, J = 8); m/z (ES+) 417 (M+H⁺).

Claims

CLAIMS:

A compound of formula I, or a salt or prodrug thereof:

R^{2/ 3}

(i)

wherein

Y represents hydrogen or d-6 alkyl; and Z represents Ci-e alkyl, C3-7 cycloalkyl, C -7 cycloalkenyl, CG-8 bicycloalkyl, aryl, C3-7 heterocycloalkyl, heteroaryl, C2-7 alkoxycarbonyl or di(Ci-6)alkylamino, any of which groups may be optionally substituted; or

Y and Z are taken together with the two intervening carbon atoms to form a ring selected from C5-9 cycloalkenyl, CG IO bicycloalkenyl, tetrahydropyridinyl, pyridinyl and phenyl, any of which rings may be optionally benzo-fused and/or substituted;

R¹ represents C3-7 cycloalkyl, phenyl, furyl, thienyl or pyridinyl, any of which groups may be optionally substituted;

R² represents hydrogen, d-G alkyl, hydroxy(Ci-6)alkyl or d-6 alkoxy(Cι-6)alkyl; and

R³ represents d-6 alkyl, C3-7 cycloalkyl(Cι-G) alkyl, aryl(Cι-6)alkyl, C3-7 heterocycloalkyl or heteroaryl(C₁-e)alkyl, any of which groups may be optionally substituted; or

R² and R³ are taken together with the intervening nitrogen atom to form a ring of formula (a), (b), (c), (d), (e), (f), (g), (h), (j) or (k):

(a) ( ) (c) (d)

(e) (f) (g) (h)

(j) ( )

wherein

X represents oxygen, sulphur, N-R⁵ or CR^GR⁷;

R⁴ represents hydrogen, Ci-e alkyl, aryl, C2-7 alkoxycarbonyl or aryl(Ci-6)alkoxy(Ci-6)alkyl; R⁵ represents hydrogen, d-6 alkyl, di(d-6)alkylamino(d-6)alkyl, C2-6 alkenyl, C3-7 cycloalkyl(d-6)alkyl, aryl, C3-7 heterocycloalkyl(d-6) alkyl, heteroaryl, C2-7 alkylcarbonyl or C2-7 alkoxycarbonyl;

R^G represents hydrogen, halogen, hydroxy, d-G alkoxy, di(d-G)alkylamino, C2-7 alkoxycarbonyl, or an optionally substituted or phenyl ring- fused C3-7 heterocycloalkyl group; and R⁷ represents hydrogen, d-6 alkyl, or an optionally substituted aryl or aryl(d-6)alkyl group.

2. A compound as claimed in claim 1 represented by formula IIA, and salts and prodrugs thereof:

(HA)

wherein R¹ is as defined in claim 1;

R¹⁸ represents hydrogen or halogen; and

Q represents the residue of a ring of formula (a), (b), (c), (d), (e), (f), (g), (h), (j) or (k) as defined in claim 1.

3. A compound as claimed in claim 1 represented by formula

IIB, and salts and prodrugs thereof:

N .

R- CH₂)_n - _R«

(UB) wherein

R¹ and R² are as defined in claim 1;

R¹⁸ is as defined in claim 2; n is 1 or 2; and

R¹³ represents hydroxy or Cι-6 alkoxy, or an optionally substituted aryl or heteroaryl group.

4. A compound as claimed in claim 3 represented by formula IIC, and pharmaceutically acceptable salts thereof:

(IIC)

wherein

R¹ and R² are as defined in claim 1;

R¹⁸ is as defined in claim 2; and

R²³ represents hydrogen, methyl or ethyl.

5. A compound as claimed in claim 1 represented by formula IID, and salts and prodrugs thereof:

(IID)

wherein

R¹ is as defined in claim 1; Q is as defined in claim 2; and

Z¹ represents Ci-r, alkyl, C3-7 cycloalkyl or aryl, any of which groups may be optionally substituted.

6. A compound as claimed in claim 1 represented by formula HE, and salts and prodrugs thereof:

. N .

R" ~(CH₂)_n - 13

R

(HE)

wherein R¹ and R² are as defined in claim 1; n and R¹³ are as defined in claim 3; and Z is as defined in claim 5.

7. A compound as claimed in claim 6 represented by formula IIF, and salts and prodrugs thereof:

(IIF)

wherein

R¹ and R² are as defined in claim 1; R²³ is as defined in claim 4; and Z¹ is as defined in claim 5.

8. A compound selected from:

3-(2-fluorophenyl)-5-(morpholin-4-yl)-[l,2,3]triazolo[l,5-α]quinazoline;

5-[5,6-dihydroimidazo[l,2-α]pyrazin-7(8H)-yl]-3-(2-fluorophenyl)-

[l,2,3]triazolo[l,5-α]quinazoline; 5-[5,6-dihydroimidazo[l,5-α]pyrazin-7(8H)-yl]-3-(2-fluorophenyl)-

[l,2,3]triazolo[l,5-α]quinazoline;

5-[5,6-dihydro[l,2,4]triazolo[l,5-α]pyrazin-7(8H)-yl]-3-(2-fluorophenyl)-

[l,2,3]triazolo[l,5-α]quinazoline;

3-(2-fluorophenyl)-5-(3-oxo-4-phenylpiperazin-l-yl)-[l,2,3]triazolo[l,5- αlquinazoline;

5-(4-ethoxycarbonylpiperazin-l-yl)-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- α]quinazoline;

5-(3-ethoxycarbonylpiperidin-l-yl)-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- α]quinazoline; 5-(4-ethoxycarbonylpiperidin-l-yl)-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- α]quinazoline;

3-(2-fluorophenyl)-5-(4-hydroxypiperidin-l-yl)-[l,2,3]triazolo[l,5- α]quinazoline; 3-(2-fluorophenyl)-5-[4-(pyridin-4-yl)piperazin-l-yl]-[l,2,3]triazolo[l,5- α] quinazoline;

3-(2-fluorophenyl)-5-[4-(pyridin-2-yl)piperazin-l-yl]-[l,2,3]triazolo[l,5- α] quinazoline;

5-(4-acetylpiperazin-l-yl)-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- α] quinazoline ;

3-(2-fluorophenyl)-5-[2-oxopiperazin-4(lH)-yl]-[l,2,3]triazolo[l,5- α] quinazoline;

3-(2-fluorophenyl)-5-(l-methyl-2-oxopiperazin-4-yl)-[l,2,3]triazolo[l,5- α] quinazoline; 5-[5,6-dihydroimidazo[l,2-α]pyrazin-7(8H)-yl]-7-fluoiO-3-(2-fluorophenyl)-

[l,2,3]triazolo[l,5-α]quinazoline;

5-[bis(2-methoxyethyl)amino]-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- α] quinazoline;

3-(2-fluorophenyl)-5-(thiomorpholin-4-yl)-[l,2,3]triazolo[l,5-α]quinazoline; 5-[4-(dimethylamino)piperidin-l-yl]-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- α] quinazoline;

3-(2-fluorophenyl)-5-[4-(pyrrolidin-l-yl)piperidin-l-yl]-[l,2,3]triazolo[l,5- α] quinazoline;

3-(2-fluorophenyl)-5-[4-(piperidin-l-yl)piperidin-l-yl]-[l,2,3]triazolo[l,5- α] quinazoline;

5-[bis(2-hydroxyethyl)amino]-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- α] quinazoline ;

3-(2-fluorophenyl)-5-(4-oxopiperidin-l-yl)-[l,2,3]triazolo[l,5-α]quinazoline;

5-(l-ethyl-2-oxopiperazin-4-yl)-3-(2-fluorophenyl)-[l,2,3]triazolo[l,5- a] quinazoline; 3-(2-fluorophenyl)-5-(2-oxo-l-propylpiperazin-4-yl)-[l,2,3]triazolo[l,5- a] quinazoline;

3-(2-fluorophenyl)-5-[2-oxo-l-(2-propenyl)piperazin-4-yl]-[l,2,3]triazolo- [1 , 5-α] quinazoline ; 3-(2-fluorophenyl)-5-(4-hydroxy-4-methylpiperidin-l-yl)-[l,2,3]triazolo-[l,5- α] quinazoline; l-{4-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin-5-yl]piperazin-l- yl}propan-l-one;

2,2-dimethyl-l-{4-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin-5- yl]piperazin-l-yl}propan-l-one; and salts and prodrugs thereof.

9. A compound selected from:

N-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin-5-yl]-N-methyl-N-(l- methylpiperidin-4-yl)amine; l-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin-5-yl]-[l,4]diazepan-5- one;

3-(2-fluorophenyl)-5-(piperidin-l-yl)-[l,2,3]triazolo[l,5-α]quinazoline;

3-(2-fluorophenyl)-5-[4-(morpholin-4-yl)piperidin-l-yl]-[l,2,3]triazolo[l,5- a] quinazoline;

4-(2-dimethylaminoethyl)-l-[3-(2-Fluorophenyl)-[l,2,3]triazolo[l,5- α] quinazolin- 5-yl] -[1,4] diazep an- 5 -one ; l'-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin-5-yl]-

[l,4']bipiperidinyl-4-carboxylic acid ethyl ester; 5-[4-(3,4-dihydro-lH-isoquinolin-2-yl)piperidin-l-yl]-3-(2-fluorophenyl)-

[l,2,3]triazolo[l,5-α]quinazoline; l-{l-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin-5-yl]piperidin-4-yl}-

[l,4]diazepan-5-one;

N,N-dimethyl-N-{l-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin-5- yl]pyrrolidin-3-yl}amine; 3-(2-fluorophenyl)-5-{4-[2-(pyrrolidin-l-yl)ethyl]piperazin-l-yl}- [l,2,3]triazolo[l,5-α]quinazoline;

3-(2-fluorophenyl)-5-(4-methoxypiperidin-l-yl)-[l,2,3]triazolo[l,5- α] quinazoline; l-cyclopropylmethyl-4-[3-(2-fluorophenyl)-[l,2,3]triazolo[l,5-α]quinazolin- 5-yl]piperazin-2-one; and salts and prodrugs thereof.

10. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof or a prodrug thereof in association with a pharmaceutically acceptable carrier.

11. The use of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof or a prodrug thereof for the manufacture of a medicament for the treatment and/or prevention of anxiety.

12. A process for the preparation of a compound of formula I as defined in claim 1, which comprises reacting a compound of formula III with a compound of formula IV:

(HI) (IV)

wherein Y, Z, R¹, R² and R³ are as defined in claim 1, and L¹ represents a suitable leaving group; and subsequently, if desired, converting a compound of formula I initially obtained into a further compound of formula I by methods known per se.

13. A method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof or a prodrug thereof.